Tibolone's Role in Glioblastoma

Tibolone (TIB) boosts growth of human glioblastoma cells, according to the results of a study published in the Archives of Medical Research. This effect is mediated via the regulation of estrogen receptors and progesterone receptors.

“Ovarian steroid hormones are involved in modulating the growth of glioblastomas through the interaction with their intracellular receptors says lead study author Aliesha Gonzalez-Arenas, Departamento de Medicina Genomica y Toxicologıa Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Ciudad Universitaria, Ciudad de Mexico, Mexico. Glioblastoma is the most common, aggressive, and lethal brain tumor, and activation of sex hormone receptors is involved in glioblastomas progression.

In the current study, investigators assessed the effect of TIB on cell number, migration, and invasion, as well as on estrogen and progesterone receptor activity and content. Two human glioblastoma cell lines, U251 MG and U87, were grown using different concentrations of tibolone, and then tested.

A 10 nM dose of TIB induced cell proliferation without affecting cell migration or invasion. This increased cell proliferation was inhibited by the estrogen or progesterone receptor antagonists ICI 182, 780, and RU 486.  The inhibition indicates that these receptors mediate the proliferation effects of TIB. Moreover, the content of these estrogen and progesterone receptors was changed by tibolone. Specifically, this agent led to an increase in ER-α, ER-ß, and PR-B, but a decrease in PR-A. Of note, estrogen receptors are synthesized as ER-α and ER-ß; whereas, progesterone and androgen receptors are synthesized as isoforms A and B, which have different cellular roles.

Tibolone is a selective tissue estrogenic activity regulator used to treat menopausal symptoms and osteoporosis. This agent is metabolized into three active metabolites: 3-α-hydroxyestrogenic, 3-ß-hydroxyestrogenic, and ▲4-keto isomer. Studies using brains from ovariectomized cynomolgus monkeys have shown that 3-hydroxy-metabolites are more frequent than ▲4-keto isomer. Estrogen receptors are bound by the 3-hydroxy-metabolites; whereas, ▲4-keto isomer binds progesterone receptors and androgen receptors.

Sex steroid hormones, progesterone, estradiol, and dihydrotestosterone help regulate tumor cell growth in the brain, along with various other pathophysiological processes. These hormones bind to their respective intracellular receptors, which are ligand-activated transcription factors. Next, steroid receptors enter the nucleus and interact with hormone response elements located in the promoter regions of target cells.

Results from a randomized-controlled trial suggested that tibolone heightened breast cancer recurrence. Furthermore, results from a literature review indicated that tibolone increases endometrial cancer risk. Such research suggests that tibolone plays a role in tumorigenesis, but more research is needed to elucidate its role in glioblastoma pathogenesis. 

Along with previous results, the investigators put findings from the current study in perspective. “We have reported that both estradiol and progesterone stimulate the proliferation, migration, invasiveness, and expression of growth factors in these cell lines derived from human glioblastoma, while TIB has an effect only on the proliferation and the expression of hormone receptors. These in vitro results indicate that further in vivo studies are necessary to interpret the possible meaning of these findings and their clinical relevance for this type of tumors.”

“Our results," they concluded, "suggest that TIB increases cell number and proliferation of human glioblastoma cells without affecting migration or invasion through the regulation of the content and activity of ERs [estrogen receptors] and PRs [progesterone receptors].”